Heterotropic Modulation of Amylin Fibrillation by Small Molecules: Implications for Formulative Designs
Celimar Sinézia, Luís Maurício T. R. Lima
The Protein Journal
Control of amylin agglomeration is of interest for both the study of pathophysiology and the design of amylin-based pharmaceutical products. Here we report the effects of a large set of common buffering agents, aminoacids and nucleoside phosphates over the amylin amyloid aggregation. Circular dichroism showed no apparent effects of the co-solutes over the secondary-structure of soluble amylin. Instead, we found a large dependence of the fibrillation process on the total amount of co-solute charged groups. The amyloid nature of the aggregates was confirmed by transmission electron microscopy, X-ray diffraction and infrared spectroscopy. While acidic pH and low-ionic co-solutes shows the largest size effect in hampering aggregation, no further effect was observed that could identify a single compound as a major direct heterotropic determinants of the amyloid process. These data suggest a more physico-chemical effect of co-solutes over the modulation of amylin instead of a chemical entity-related causal factor.
Circular dichroism, Secondary structure, Chemical stability, Biochemistry